Stable microbubbles suspensions injectable into living organisms

• US 5,380,519 A
• Filed: 09/29/1993
• Issued: 01/10/1995
• Est. Priority Date: 04/02/1990
• Status: Expired due to Term

• Current Assignee: Bracco Suisse SA
• Original Assignee: Bracco International B.V. (Bracco SPA)
• Inventors: Bussat, Philippe, Schneider, Michel, Bichon, Daniel, Puginier, Jerome, Hybl-Sutherland, Eva
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US08/128,540
• Time in Patent Office: 468 Days
• Field of Search: 424/9, 424/450, 514/975, 128/662.02
• US Class Current: 424/9.51
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric

Abstract

Gas or air filled microbubble suspensions in aqueous phase usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.

Claims

1. A dry pulverulent formulation which, upon dissolution in water, will form an aqueous suspension of microbubbles for ultrasonic echography, said formulation comprising one or more film forming surfactants selected from the group consisting of phosphatidic acid, phosphatidyl-choline, phosphatidyl-serine, phosphatidyl-ethanolamine, phosphatidyl-glycerol, phosphatidyl-inositol, cardiolipin, sphingomyelin, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopherol, dicetyl-phosphate, propyl gallate, ascorbyl palmitate, butylated hydroxy-toluene and mixtures thereof in laminar form and one or more hydrosoluble stabilizers selected from the group consisting of linear and cross-linked poly- and oligosaccharides, sugars and hydrophilic polymers.

2. The formulation of claim 1, wherein said surfactants comprise up to 50% by weight non-laminar surfactants selected from the group consisting of fatty acids, esters, ethers of fatty acids, alcohols with polyols and polyalkylenated glycerol.

3. The formulation of claim 2, wherein said surfactants comprise polyalkylene glycols and polyalkylenated sugars.

4. The formulation of claim 1, wherein the hydrosoluble stabilizers are present in a weight ratio to the surfactants of between about 1:

5 to 100;

1.

5. The formulation of claim 1, wherein the suspension contains about 10⁷ -10¹¹ microbubbles/ml of 0.5-10 μ

m size/ml.

6. The formulation of claim 5, wherein the suspension contains about 10⁸ -10⁹ microbubbles/ml.

7. The formulation of claim 1, in which the surfactants in laminar form are in the form of fine layers deposited on the surface of soluble or insoluble solid particulate material.

8. The formulation of claim 7, in which the insoluble solid particles are glass or polymer beads.

9. The formulation of claim 7, in which the soluble particles are made of hydrosoluble carbohydrates, polysaccharides, synthetic polymers, albumin, gelatin or Iopamidol.

10. The formulation of claim 1, comprising freeze-dried lyposomes.